EP0906118A1 - Method for treating inflammation - Google Patents
Method for treating inflammationInfo
- Publication number
- EP0906118A1 EP0906118A1 EP97922413A EP97922413A EP0906118A1 EP 0906118 A1 EP0906118 A1 EP 0906118A1 EP 97922413 A EP97922413 A EP 97922413A EP 97922413 A EP97922413 A EP 97922413A EP 0906118 A1 EP0906118 A1 EP 0906118A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- steroid
- inflammatory
- septic shock
- administered
- combination
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2066—IL-10
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- This invention relates to a method for treating inflammatory conditions or diseases relating to inflammation, Including septic shock.
- cytokines mediate numerous immune/inflammatory responses.
- cytokines such as tumor necrosis factor alpha (TNF- ⁇ ), lnterleukin-1 (IL- 1 ), Interferon gamma (IFN-7), and lnterleukin-6 (IL-6)
- TNF- ⁇ tumor necrosis factor alpha
- IL- 1 lnterleukin-1
- IFN-7 Interferon gamma
- IL-6 lnterleukin-6
- Septic shock is one example of a disease state characterized by production of inflammatory cytokines. It is an often fatal condition usually resulting from gram-negative bacteremia. Despite the use of potent antibiotics and intensive care, there is still a high mortality rate for sepsis as well as for cases of gram-negative bacteremia which result in septic shock (See, e.g., Ziegler et al., New Eng. J. Med. 324:429 (1991); Bone et al., New Eng. J. Med. 377:653 (1987); and Kreger er a/., Am. J. Med 68:344 (1980)).
- TNF-a tumor necrosis factor
- IL-1 lnterleukin-1
- LPS lipopolysacchride
- inflammatory conditions treatable or preventable by this invention are those caused by auto-immune diseases which exhibit inflammation as a symptom, such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, uveitis, psoriasis, etc.
- This invention fills the foregoing need by providing a method for treating or preventing inflammatory conditions in a mammal comprising administering an effective amount of a combination of IL-10 and at least one steroid to a mammal in need of such treatment.
- this invention provides a method for treating or preventing septic shock, or an autoimmune disease such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, uveitis and psoriasis, in a mammal comprising administering an effective amount of a combination of IL-10 and at least one steroid to a mammal in need of such treatment.
- This invention also is directed at the use of a combination of IL-10 and a steroid for the manufacture of a medicament for the treatment of inflammatory disease in a mammal.
- a pharmaceutical composition comprising a combination of IL-10 and at least one steroid, and a physiologically acceptable carrier.
- Yet another aspect of this invention is a kit for treating or preventing an inflammatory condition in a mammal comprising in combination an effective amount of IL-10 admixed with a pharmaceutical carrier and an effective amount of a steroid admixed with a pharmaceutically carrier.
- Figure 1 illustrates the in vivo effect of recombinant IL-10 and/or the steroid betamethasone phosphate on LPS (lipopolysaccharide)-induced serum IL-1 in mice primed with C. parvum.
- LPS lipopolysaccharide
- the data marked with double asterisks indicate P ⁇ 0.05 compared to PBS/Tween/MSA.
- Figure 2 illustrates the in vivo effect of recombinant IL-10 and/or the steroid betamethasone phosphate on LPS-induced serum IL-6 in mice primed with C. parvum.
- the data marked with double asterisks indicate P ⁇ 0.01 compared to PBSATween/MSA.
- Figure 3 illustrates the in vivo effect of recombinant IL-10 and/or the steroid betamethasone phosphate on LPS-induced serum TNF- ⁇ in mice primed with C. parvum.
- the data marked with double asterisks indicate P
- Figure 4 illustrates the in vivo effect of recombinant IL-10 and/or the steroid betamethasone phosphate on LPS-induced serum IFN-Y in mice primed with C. parvum. The data marked with double asterisks indicate P
- Figure 5 illustrates the results of another experiment for mean inhibition of four serum cytokines in mice treated with betamethasone phosphate and recombinant human IL-10 in combination (the present invention), IL-10 alone, and betamethasone phosphate alone.
- interleukin-10 or "IL-10” is defined as a protein which (a) has an amino acid sequence of mature IL-10 (e.g., lacking a secretory leader sequence) as disclosed in U.S. Patent No. 5,231 ,012 and (b) has biological activity that is common to native IL-10. Also included are muteins and other analogs, including the Epstein-Barr Virus protein BCRF1 (viral IL-10), which retain the biological activity of IL-10.
- BCRF1 Epstein-Barr Virus protein
- IL-10 suitable for use in the invention can be obtained from culture medium conditioned by activated cells secreting the protein, and purified by standard methods. Additionally, the IL-10, or active fragments thereof, can be chemically synthesized using standard techniques known in the art. See Merrifield, Science 233:341 (1986) and Atherton er al., Solid Phase Peptide Synthesis: A Practical Approach, 1989, 1.R.L. Press, Oxford. See also U.S. Patent No. 5,231 ,012.
- the protein or polypeptide is obtained by recombinant techniques using isolated nucleic acid encoding the IL-10 polypeptide.
- General methods of molecular biology are described, e.g., by Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor, New York, 2d ed., 1989, and by Ausubel et al., (eds.) Current Protocols in Molecular Biology, Green/Woley, New York (1987 and periodic supplements).
- the appropriate sequences can be obtained using standard techniques from either genomic or cDNA libraries. Polymerase chain reaction (PCR) techniques can be used. See, e.g., PCR Protocols: A Guide to Methods and Applications, 1990, Innis er a/., (Ed.), Academic Press, New York, New York.
- Libraries are constructed from nucleic acid extracted from appropriate cells. See, e.g., U.S. Patent No. 5,231 ,012, which discloses recombinant methods for making IL-10.
- Useful gene sequences can be found, e.g., in various sequence databases, e.g., GenBank and BMPL or nucleic acid and PIR and Swiss-Prot for protein, c/o Intelligenetics,
- Clones comprising sequences that encode human IL-10 have been deposited with the American Type Culture Collection (ATCC), Rockville, Maryland, under Accession Nos. 68191 and 68192. Identification of other clones harboring the sequences encoding IL-10 is performed by either nucleic acid hybridization or immunological detection of the encoded protein, if an expression vector is used. Oligonucleotide probes based on the deposited sequences disclosed in U.S. Patent No. 5,231 ,012 are particularly useful. Oligonucleotide probes sequences can also be prepared from conserved regions of related genes in other species. Alternatively, degenerate probes based on the amino acid sequences of IL-10 can be used.
- Standard methods can be used to produce transformed prokaryotic, mammalian, yeast or insect cell lines which express large quantities of the polypeptide.
- Exemplary E. coli strains suitable for both expression and cloning include W3110 (ATCC Bi, 27325), X1776 (ATCC No. 31244). X2282, and RR1 (ATCC Mp/ 31343).
- Exemplary mammalian cell lines include COS-7 cells, mouse L cells and CHP cells. See Sambrook (1989), supra and Ausubel et al., 1987 supplements, supra.
- Various expression vectors can be used to express DNA encoding IL-10.
- Conventional vectors used for expression of recombinant proteins in prokaryotic or eukaryotic cells may be used.
- Preferred vectors include the pcD vectors described by Okayama et al., Mol. Cell. Biol. 3:280 (1983); and Takebe et al., Mol. Cell. Biol. 3:466 (1988).
- Other SV40-based mammalian expression vectors include those disclosed in Kaufman et al., Mol. Cell. Biol. 2:1304 (1982) and U.S. Patent No. 4,675,285. These SV40-based vectors are particularly useful in COS-7 monkey cells (ATCC No.
- the IL-10 may be produced in soluble form, such as a secreted product of transformed or transfected yeast, insect or mammalian cells.
- the peptides can then be purified by standard procedures that are known in the art. For example, purification steps could include ammonium sulfate precipitation, ion exchange chromatography, gel filtration, electrophoresis, affinity chromatography, and the like. See Methods in Enzymology Purification Principles and Practices (Springer- Verlag, New York, 1982).
- IL-10 may be produced in insoluble form, such as aggregates or inclusion bodies.
- the IL-10 in such a form is purified by standard procedures that are well known in the art. Examples of purification steps include separating the inclusion bodies from disrupted host cells by centrifugation, and then solubilizing the inclusion bodies with chaotropic agent and reducing agent so that the peptide assumes a biologically active conformation. For specifics of these procedures, see, e.g. Winkler et al., Biochemistry 25:4041 (1986), Winkler et al.,
- the nucleotide sequences used to transfect the host cells can be modified using standard techniques to make IL-10 or fragments thereof with a variety of desired properties.
- modified IL-10 can vary from the naturally-occurring sequences at the primary structure level, e.g., by amino acid, insertions, substitutions, deletions and fusions. These modifications can be used in a number of combinations to produce the final modified protein chain.
- the amino acid sequence variants can be prepared with various objectives in mind, including increasing serum half-life, facilitating purification or preparation, improving therapeutic efficacy, and lessening the severity or occurrence of side effects during therapeutic use.
- the amino acid sequence variants are usually predetermined variants not found in nature, although others may be post-translational variants. Such variants can be used in this invention as long as they retain the biological activity of IL-10.
- human IL-10 is used for the treatment of humans, although viral IL-10 could possibly be used. Most preferably, the IL-10 used is recombinant human IL-10.
- the preparation of human IL-10 has been described in U.S. Patent No. 5,231 ,012.
- the cloning and expression of viral IL-10 (BCRF1 protein) from Epstein-Barr virus has been disclosed by Moore et al., Science 243:1230 (1990).
- Active fragments, analogs and homologs to IL-10 include those proteins, polypeptides, or peptides which possess one or more various characteristic IL-10 activities.
- Examples of IL-10 activity include inhibition or substantial reduction of the level of IL-2, lymphotoxin, IL-3, or GM-CSF.
- IL-10 activity also includes inhibition of cytokine production by activated macrophages, e.g., IL-1 , IL-6, and TNF-a.
- Steroids suitable for use in this invention include glucocorticoids.
- glucocorticoids include prednisone, dexamethasone, fluticasone, betamethasone, and other steroids and derivatives thereof.
- the steroid used was betamethasone phosphate in a buffered saline solution.
- Betamethasone derivatives are commercially available from Schering Corporation, Kenilworth, New Jersey.
- the IL-10 is preferably combined in the same composition with the steroid.
- the combination of IL-10 plus steroid can be achieved by any means of co- administration.
- the co-administration can be sequential or simultaneous.
- “Co-administration” generally means that the multiple (two or more) therapeutics are present in the recipient during a specified time interval. Typically, if a second agent is administered within the half-life of the first agent, the two agents are considered co-administered.
- the invention further provides a method of predicting a mammal's predisposition for development of an inflammatory condition, characterized by suboptimal levels of IL-10, comprising assaying a sample taken from a mammal for an IL-10 level.
- Suboptimal levels include undetectable amounts.
- a detectable level could be compared to a known normal level of IL-10.
- blood is the sample source. The method allows for prediction of predisposition to a number of inflammatory conditions, such as inflammatory bowel disease, rheumatoid arthritis, or psoriasis.
- compositions including IL-10 and a steroid are admixed with a pharmaceutically acceptable carrier or excipient which is preferably inert.
- a pharmaceutical carrier can be any compatible non-toxic substance suitable for delivery of the polypeptide to a patient. Preparation of such pharmaceutical compositions is known in the art; see, e.g., Remington's Pharmaceutical Sciences, and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).
- the proportion of IL-10, steroid and additive can be varied over a broad range so long as both are present in therapeutically effective amounts.
- the amount of the IL-10 will preferably range from about 0.5 to 15 ⁇ g/KG of body weight, and the amount of steroid can range from about 0.5 to 50 mg, more preferably 2 to 12 and most preferably 5 to 12 mg.
- compositions may be ingested orally or injected into the body.
- Formulations for oral use include compounds to protect the polypeptides from proteases which occur in the gastrointestinal tract. Injections are usually intramuscular, subcutaneous, intradermal or intravenous. Alternatively, intra-articular injection or other routes could be used in appropriate circumstances.
- compositions When administered parenterally, the compositions can be formulated in a unit dosage injectable form (solution, suspension, emulsion) in association with a pharmaceutical carrier.
- a pharmaceutical carrier for instance, the IL-10 and steroid may be administered in aqueous vehicles such as water, saline or buffered vehicles with or without various additives and/or diluting agents.
- suitable carriers are normal saline, Ringer's solution, dextrose solution, and Hank's solution.
- Non-aqueous carriers such as fixed oils and ethyl oleate may also be used.
- a preferred carrier is 5% dextrose/saline.
- the carrier may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives.
- the IL-10 in the composition is preferably formulated in purified form substantially free of aggregates and other proteins.
- a suspension such as a zinc suspension, can be prepared to include the polypeptide. Such a suspension can be useful for subcutaneous (SQ) or intramuscular (IM) injection.
- the phrase "therapeutically effective amount” means an amount sufficient to ameliorate a symptom or sign of a given inflammatory condition.
- the signs and symptoms include one or more of pain, swelling, redness and other well known signs and symptoms of inflammation.
- the signs and symptoms are one or more of hypertension, microthrombi, organ failure, loss of plasma due to increased vascular permeability, as well as other known signs and symptoms of septic shock.
- prevention of inflammatory conditions can be defined by the following parameters. Certain circumstances pre-dispose individuals to developing inflammatory conditions such as septic shock. For example, candidates for abdominal surgery, or any situation that would cause the rupture of or laceration of the intestines (i.e., ruptured appendix) that would entail a leakage of intestinal microflora into the abdominal cavity. Other examples include gun shot wounds, automobile accident victims with abdominal trauma, and the like. Administration of IL-10 plus at least one steroid to such individuals at high risk for developing an inflammatory condition such as septic shock prior to the onset of symptoms would ameliorate such symptoms, preventing the actual onset of the full blown manifestations of the disease.
- Typical mammals that can be treated using the methods of the present invention include companion animals such as dogs and cats, and primates, including humans.
- IL-10 derived from the species of the treatment target animal will be used.
- An effective amount for a particular patient may vary depending on factors such as the condition being treated, the overall health of the patient, the method, route, and dose of administration and the severity of side effects. Determination of the appropriate dose is made by the clinician using parameters known in the art. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved. (See generally The Merck Manual ⁇ 269 "Pharmacokinetics and Drug Administration.”).
- the preferred total daily dose of IL-10 and steroid is selected from a range of about 0.5 to 9 mg of an injectable steroid, 2.5 to 50 mg of an orally administered steroid, and 2 to 15 ⁇ g/KG of body weight of IL-10. Dosages are on a schedule which effects the desired treatment and can be periodic over short or longer term. The daily infusion rate may be varied based on monitoring of side effects, blood cell counts, and efficacy. See Gilman et al. (eds.) (1990) Goodman and Gilman's: The Pharmacological Bases of Therapeutics 8th ed., Pergamon Press;(1990) Remington's Pharmaceutical Sciences.
- the therapeutically effective amount is a unit dose presented in an ampoule.
- the therapeutically effective amount could be presented in a vial containing multiple doses or it could be offered in some other form.
- the total daily dose may be given as a single injection, a continuous infusion, or it may be divided into several smaller doses for bolus intravenous administration or administration by some other route such as intramuscular injection.
- Compositions of the invention may also be introduced into a patient's body by an implantable or injectable drug delivery system, e.g., Urquhart et al., Ann. Rev.
- multiple medications can be administered in combination.
- the IL-10 and steroid combination can be administered in further combination with a therapeutically effective dose of one or more additional therapeutically active agents.
- mice in each group were primed with 0.5 mg heat-killed C. parvum, (I.V. administration) as a challenge.
- PBS phosphate buffered saline
- Tween 20 trademark or tradename
- MSA mouse serum albumin
- a second group was treated with 0.1 mg/KG betamethasone phosphate in buffered saline p.o. one hour before challenge.
- a third group was treated with 1 ⁇ g recombinant human IL-10 (rHulL-10) i.p. at time of challenge.
- another group was treated with 0.1 mg/KG betamethasone phosphate in buffered saline p.o. one hour before challenge and 1 ⁇ g rHulL-10 i.p. at time of challenge.
- the combination of IL-10 and steroid reduced the amount of inflammation-causing agent by more than either the steroid or IL-10 alone. Furthermore, in this experiment, the combined IL-10 and steroid exerted a synergistic effect in lowering the concentration of at least one inflammation-causing agent, TNF- ⁇ .
- the present invention provides a method of treating or preventing inflammation, including toxic shock, that is more effective than administration of either a steroid or IL- 10 alone.
- the invention is expected to have the advantage of eliminating of reducing the well-known side effects of steroids, such as liver damage, kidney damage and increased susceptibility to infection. This advantage will result from the use of smaller amounts of steroid or a shorter course of treatment which the additive and/or synergistic combination of IL-10 and a steroid will provide.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US642816 | 1991-01-18 | ||
US08/642,816 US5753218A (en) | 1996-05-03 | 1996-05-03 | Method for treating inflammation |
PCT/US1997/006802 WO1997041882A1 (en) | 1996-05-03 | 1997-04-29 | Method for treating inflammation |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0906118A1 true EP0906118A1 (en) | 1999-04-07 |
Family
ID=24578143
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97922413A Ceased EP0906118A1 (en) | 1996-05-03 | 1997-04-29 | Method for treating inflammation |
Country Status (15)
Country | Link |
---|---|
US (1) | US5753218A (en) |
EP (1) | EP0906118A1 (en) |
JP (1) | JP2000509715A (en) |
KR (1) | KR20000010706A (en) |
AR (1) | AR006932A1 (en) |
AU (1) | AU718857B2 (en) |
BR (1) | BR9708908A (en) |
CA (1) | CA2253312A1 (en) |
HU (1) | HUP9903144A3 (en) |
ID (1) | ID17194A (en) |
IL (1) | IL126759A0 (en) |
NZ (1) | NZ332464A (en) |
PE (1) | PE64498A1 (en) |
WO (1) | WO1997041882A1 (en) |
ZA (1) | ZA973707B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997014484A1 (en) | 1995-10-20 | 1997-04-24 | Melvin Molnick | Method of participating in a live casino game from a remote location |
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US6861053B1 (en) | 1999-08-11 | 2005-03-01 | Cedars-Sinai Medical Center | Methods of diagnosing or treating irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth |
US7048906B2 (en) * | 1995-05-17 | 2006-05-23 | Cedars-Sinai Medical Center | Methods of diagnosing and treating small intestinal bacterial overgrowth (SIBO) and SIBO-related conditions |
US6562629B1 (en) | 1999-08-11 | 2003-05-13 | Cedars-Sinai Medical Center | Method of diagnosing irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth by detecting the presence of anti-saccharomyces cerivisiae antibodies (asca) in human serum |
US7067144B2 (en) * | 1998-10-20 | 2006-06-27 | Omeros Corporation | Compositions and methods for systemic inhibition of cartilage degradation |
JP2002541210A (en) * | 1999-04-13 | 2002-12-03 | シェーリング コーポレイション | Novel use of mammalian OX2 protein and related reagents |
US6544504B1 (en) | 1999-07-28 | 2003-04-08 | Schering Corporation | Combined use of interleukin 10 and methotrexate for immuno-modulatory therapy |
WO2001008696A2 (en) * | 1999-07-28 | 2001-02-08 | Schering Corporation | Combined use of interleukin 10 and methotrexate for immuno-modulatory therapy |
AU6517900A (en) * | 1999-08-03 | 2001-02-19 | Smith & Nephew, Inc. | Controlled release implantable devices |
US20040063685A1 (en) * | 2000-12-08 | 2004-04-01 | Juji Ilzawa | Combination Drugs |
US6667344B2 (en) | 2001-04-17 | 2003-12-23 | Dey, L.P. | Bronchodilating compositions and methods |
US20030103941A1 (en) * | 2001-10-09 | 2003-06-05 | Crombleholme Timothy M. | Materials and methods for preventing or reducing scar formation |
AU2002352925A1 (en) * | 2001-11-28 | 2003-06-10 | Schering Corporation | Method for treating and preventing pancreatitis |
US20040023935A1 (en) * | 2002-08-02 | 2004-02-05 | Dey, L.P. | Inhalation compositions, methods of use thereof, and process for preparation of same |
US20040109826A1 (en) * | 2002-12-06 | 2004-06-10 | Dey, L.P. | Stabilized albuterol compositions and method of preparation thereof |
TWI359675B (en) | 2003-07-10 | 2012-03-11 | Dey L P | Bronchodilating β-agonist compositions |
US20120195938A1 (en) * | 2007-05-30 | 2012-08-02 | James Louis Rutkowski | Formulations and methods for recovery from dental surgery |
US9511076B2 (en) * | 2008-05-30 | 2016-12-06 | Clarion Research Group | Formulations and methods for recovery from dental surgery |
EP2654756A1 (en) * | 2010-12-22 | 2013-10-30 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Compound having antibacterial activity |
KR20160083884A (en) | 2013-11-01 | 2016-07-12 | 스페리움 바이오메드 에스.엘. | Inclusion bodies for transdermal delivery of therapeutic and cosmetic agents |
KR102624174B1 (en) * | 2020-09-18 | 2024-01-23 | 주식회사 아미코젠파마 | Pharmaceutical composition comprising aqueous solubilized bile acid for the prevention or treatment of sepsis, acute lung injury disease, or acute respiratory distress syndrome |
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US5008374A (en) * | 1986-03-14 | 1991-04-16 | Otsuka Pharmaceutical Co., Ltd. | IL-1α derivatives and drugs |
WO1989004838A1 (en) * | 1987-11-25 | 1989-06-01 | Immunex Corporation | Interleukin-1 receptors |
US5077284A (en) * | 1988-12-30 | 1991-12-31 | Loria Roger M | Use of dehydroepiandrosterone to improve immune response |
US5231012A (en) * | 1989-06-28 | 1993-07-27 | Schering Corporation | Nucleic acids encoding cytokine synthesis inhibitory factor (interleukin-10) |
US5449515A (en) * | 1989-11-21 | 1995-09-12 | University Of Melbourne | Anti-inflammatory compositions and methods |
US5300292A (en) * | 1991-05-03 | 1994-04-05 | The Regents Of The University Of California | Composition and method for treating inflammation |
JPH07502019A (en) * | 1991-08-06 | 1995-03-02 | シェリング・コーポレーション | Use of interleukin-10 analogs or antagonists to treat endotoxin- or superantigen-induced toxicity |
US5368854A (en) * | 1992-08-20 | 1994-11-29 | Schering Corporation | Use of IL-10 to treat inflammatory bowel disease |
US5601815A (en) * | 1992-08-21 | 1997-02-11 | Schering Corp | IL-4 and IL-10 to downregulate delayed-type hypersensitivity and cytokine expresion by T-cells |
AU6763496A (en) * | 1995-08-07 | 1997-03-05 | Schering Corporation | Treatment of ocular inflammatory conditions with interleukin-10 |
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1996
- 1996-05-03 US US08/642,816 patent/US5753218A/en not_active Expired - Fee Related
-
1997
- 1997-04-29 CA CA002253312A patent/CA2253312A1/en not_active Abandoned
- 1997-04-29 ZA ZA9703707A patent/ZA973707B/en unknown
- 1997-04-29 AU AU28089/97A patent/AU718857B2/en not_active Ceased
- 1997-04-29 JP JP9539946A patent/JP2000509715A/en active Pending
- 1997-04-29 HU HU9903144A patent/HUP9903144A3/en unknown
- 1997-04-29 EP EP97922413A patent/EP0906118A1/en not_active Ceased
- 1997-04-29 KR KR1019980708807A patent/KR20000010706A/en active IP Right Grant
- 1997-04-29 IL IL12675997A patent/IL126759A0/en unknown
- 1997-04-29 PE PE1997000324A patent/PE64498A1/en not_active Application Discontinuation
- 1997-04-29 NZ NZ332464A patent/NZ332464A/en unknown
- 1997-04-29 BR BR9708908A patent/BR9708908A/en not_active Application Discontinuation
- 1997-04-29 WO PCT/US1997/006802 patent/WO1997041882A1/en active IP Right Grant
- 1997-04-30 AR ARP970101806A patent/AR006932A1/en unknown
- 1997-04-30 ID IDP971448A patent/ID17194A/en unknown
Non-Patent Citations (1)
Title |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1997014484A1 (en) | 1995-10-20 | 1997-04-24 | Melvin Molnick | Method of participating in a live casino game from a remote location |
Also Published As
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ZA973707B (en) | 1997-10-29 |
AR006932A1 (en) | 1999-09-29 |
US5753218A (en) | 1998-05-19 |
NZ332464A (en) | 2000-07-28 |
HUP9903144A3 (en) | 2000-11-28 |
KR20000010706A (en) | 2000-02-25 |
ID17194A (en) | 1997-12-11 |
WO1997041882A1 (en) | 1997-11-13 |
AU718857B2 (en) | 2000-04-20 |
JP2000509715A (en) | 2000-08-02 |
IL126759A0 (en) | 1999-08-17 |
PE64498A1 (en) | 1998-10-29 |
AU2808997A (en) | 1997-11-26 |
BR9708908A (en) | 1999-08-03 |
CA2253312A1 (en) | 1997-11-13 |
HUP9903144A2 (en) | 2000-03-28 |
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